Methods of applying coating materials for solid medicines

ABSTRACT

A method improves stability of drugs in a solid pharmaceutical formulation against oxygen and water vapor by coating the solid pharmaceutical formulation with a coating material including a high hydrogen-bonding resin and a swelling clay.

RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 13/141,168 filed Jun.21, 2011, which is a §371 of International Application No.PCT/JP2009/071573, with an international filing date of Dec. 25, 2009(WO 2010/074223 A1, published Jul. 1, 2010), which is based on JapanesePatent Application No. 2008-329678, filed Dec. 25, 2008, the subjectmatter of which is incorporated by reference.

TECHNICAL FIELD

This disclosure relates to a coating material (coating agent) for asolid formulation and methods of applying coating materials for solidmedicines.

BACKGROUND

It is known that many pharmaceuticals are not stable against oxygen andwater vapor and that some change occurs in about 40% of pharmaceuticalswhen they are left to stand in unpacked condition, thereby causing afatal problem in the pharmaceutical quality. Therefore, most of thecommercially available pharmaceuticals, especially solid formulations,are packaged with a packaging material such as PTP (press through pack)sheet and protected from oxygen and water vapor. In recent years, PTPsheets in which polyvinylidene chloride having superior water vaporbarrier property (moisture resistance) and oxygen barrier property arelaminated have been developed and put into practice.

As a method of improving the stability of a solid formulation againstoxygen and water vapor, methods of sugar-coating the solid formulationand methods of film-coating the solid formulation with a macromolecularsubstance have been put into practice. In the latter film-coatingmethods, polyvinyl alcohols and sodium carboxymethyl cellulose are knownas a macromolecular substance exhibiting oxygen barrier property, and asa macromolecular substance exhibiting water vapor barrier property,aminoalkyl methacrylate copolymer E (Eudragit EPO (registeredtrademark); Degusssa Co.) is known.

Recently, as a macromolecular substance having an improved oxygenbarrier property, a resin composition obtained by copolymerizing apolyvinyl alcohol and a polymerizable vinyl monomer (WO 05/019286) and acoating material obtained by adding talc and a surfactant to a polyvinylalcohol (JP 2006-188490 A) have been developed to try to improve thestability of solid formulations. In addition, in the field of packagingfilms, as a method of improving gas barrier properties (oxygen barrierproperty and water vapor barrier property) in high humidity, methods ofdispersing an intercalation compound in a polyvinyl alcohol have beenproposed (JP 11-315222 A and JP 9-150484 A).

Meanwhile, at medical sites and dispensing pharmacies, to preventpatients from forgetting to take their prescribed drugs or makingmistakes in the dosage thereof, it is widely practiced to usesingle-dose formulation which is prepared by taking a plurality ofpharmaceuticals to be taken at once out of the respective packagingmaterial such as PTP sheet and provides them altogether in one bag.

However, in those pharmaceuticals used in single-dose formulations,although the stability against oxygen and water vapor is ensured by thepackaging material such as PTP sheet at the stage when thepharmaceuticals are put onto the market, since they are stored inunpacked condition over a prolonged period at medical scenes and thelike, there is a risk of causing a deterioration in the quality of thepharmaceuticals.

To avoid this risk, there is a method of sugar-coating a solidformulation. However, sugar-coating of a solid formulation not onlyrequires a long processing time, but also makes the resulting solidformulation excessively large, rendering it difficult for patients totake. Consequently, there are currently limited cases where this methodis applicable. In addition, at present, the existing methods offilm-coating a solid formulation cannot allow the resulting solidformulation to exhibit sufficient oxygen barrier property in highhumidity, and even when the resin composition according to WO '286 isused, the resulting oxygen barrier property falls short of that of apackaging material such as PTP sheet. In the field of packaging films,there are coating materials having superior oxygen barrier property.However, they cannot be applied to a solid formulation since they arelaminated films with a substrate film.

In view of the above, it could be helpful to provide a coating materialfor a solid formulation which is capable of stably retaining the qualityof the effective ingredient in the solid formulation for a prolongedperiod even in unpacked condition in such a manner that the solidformulation can be used in a single-dose formulation.

SUMMARY

We intensively studied the possibility that a coating material in whicha swelling clay forms specific laminated structures in highhydrogen-bonding resin imparts gas barrier properties equivalent orsuperior to those of a PTP sheet (oxygen permeability coefficient: lessthan 1×10⁻⁴ cm³·mm/cm²·24 hr·atm; water vapor permeability: less than1×10⁻⁴ g·mm/cm²·24 hr·atm) to a solid formulation.

We thus provide a coating material for a solid formulation whichcomprises a high hydrogen-bonding resin and a swelling clay. When thiscoating material is applied (coated) on a solid formulation and dried, acoating film in which the laminated structures of the aforementionedswelling clay are oriented planarly and dispersed in a network fashionis formed, so that the gas barrier properties of the coating materialcan be improved to a level equivalent or superior to those of a PTPpackaging material. In addition, since the formed coating film isthinner than a sugar coat, the taking of the formulation by patients isnot adversely affected as well.

In the aforementioned coating material, it is preferred that the ratioof the area occupied by the aforementioned planarly-oriented laminatedstructures be not less than 30% with respect to the area of thelongitudinal section of the aforementioned coating film, and it is morepreferred that the mass ratio of the high hydrogen-bonding resin and theswelling clay be 4:6 to 6:4. In this case, since the laminatedstructures of the swelling clay become likely to intertwine with eachother, the gas barrier properties of the resulting coating film can befurther improved.

Further, it is preferred that the aforementioned coating materialcomprise a sugar alcohol derivative-type surfactant. In this case, it ispreferred that the mass ratio of the aforementioned highhydrogen-bonding resin and the aforementioned swelling clay be 2:8 to5:5 and that the content of the aforementioned sugar alcoholderivative-type surfactant be 7 to 35%. When the aforementioned coatingmaterial comprises a sugar alcohol derivative-type surfactant, since theoxygen permeability coefficient and water vapor permeability of theformed coating film can be further decreased, the stability of theeffective ingredient in the solid formulation against oxygen and watervapor can be further improved.

It is preferred that the aforementioned high hydrogen-bonding resin be apolyvinyl alcohol and that the aforementioned swelling clay be abentonite. The polyvinyl alcohol improves the oxygen barrier property inlow humidity and the bentonite is oriented planarly in parallel to thesurface direction of the high hydrogen-bonding resin layer to producepath effect, so that the gas barrier properties in high humidity can beimproved.

It is preferred that the aforementioned sugar alcohol derivative-typesurfactant be a sorbitan fatty acid ester. When the aforementionedcoating material comprises a sorbitan fatty acid ester, since thedispersion of the swelling clay is improved, the gas barrier propertiescan be improved.

Further, we provide a solid formulation coated with the aforementionedcoating material. This solid formulation can retain the stability of theeffective ingredient therein for a prolonged period even in unpackedcondition in such a manner that the solid formulation can be used in asingle-dose formulation.

A solid formulation can thus be coated with a thin coating film in sucha manner that the taking thereof is not adversely affected, and gasbarrier properties equivalent or superior to those of a packagingmaterial such as PTP sheet can be imparted. Therefore, the solidformulation coated with the aforementioned coating material can retainthe stability of the effective ingredient in the solid formulation for aprolonged period even in unpacked condition, so that the solidformulation can be used in single-dose formulation without causing adeterioration in the quality of the pharmaceutical.

Further, since the coating material has excellent moisture resistanceand excellent disintegration property at the same time, it may beapplied in coating not only sustained release formulations, but alsoimmediate release formulations. In addition, since the coating materialcan be produced using a coating machine commonly used by those skilledin the art such as a continuous aeration coating machine, fluidized bedcoating machine or pan coater, the coating material may be widely usedand the coating operation thereof on a solid formulation can be easilycarried out.

We provide a method of improving stability of drugs in a solidpharmaceutical formulation against oxygen and water vapor includingcoating the solid pharmaceutical formulation with a coating materialincluding a high hydrogen-bonding resin and a swelling clay.

We also provide a method of improving gas barrier properties of a solidpharmaceutical formulation against oxygen and water vapor includingcoating the solid pharmaceutical formulation with a coating materialincluding a high hydrogen-bonding resin and a swelling clay.

We further provide a method according of film-coating a solidpharmaceutical formulation comprising applying a coating materialincluding a high hydrogen-bonding resin in a swelling clay to the solidpharmaceutical formulation.

Also, we provide a method of manufacturing a solid pharmaceuticalformulation comprising coating the solid pharmaceutical formulation witha coating material including a high hydrogen-bonding resin and aswelling clay.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a focused ion beam-transmission electron micrograph of thecoating film of Example 1.

FIG. 2 shows a focused ion beam-transmission electron micrograph of thecoating film of Example 2.

FIG. 3 shows a focused ion beam-transmission electron micrograph of thecoating film of Example 3.

FIG. 4 shows a focused ion beam-transmission electron micrograph of thecoating film of Comparative Example 4.

FIG. 5 shows a focused ion beam-transmission electron micrograph of thecoating film of Comparative Example 5.

FIG. 6 is a graph showing the changes with time in the drug residualratio of the ascorbic acid tablet.

FIG. 7 is a graph showing the changes with time in the drug residualratio of the propantheline bromide tablet.

DETAILED DESCRIPTION

Preferred examples will now be described. However, this disclosure isnot restricted to those examples and, unless otherwise specified, theunit “%” represents “mass-to-mass percentage (w/w %).”

The coating material is characterized by comprising a highhydrogen-bonding resin and a swelling clay. When the coating material iscoated on a solid formulation and dried, since a coating film in whichthe laminated structures of the aforementioned swelling clay areoriented planarly and dispersed in a network fashion is formed, the gasbarrier properties of the coating material can be improved to a levelequivalent or superior to those of a PTP packaging material.

The term “coating material” refers to a composition which forms a thincoating film when coated on a solid formulation, thereby preventing theeffective ingredient contained in the solid formulation from beingdegraded or the like by oxygen, water, light or the like. Theaforementioned coating material can be prepared by dispersing it in anappropriate solvent in accordance with the intended use and utilized tocoat a solid formulation and produce a coating film or film formulation.A coating film can be obtained by drying the solvent (water and thelike) from the coating material or a solution containing the coatingmaterial, and a film formulation can be obtained by adding an effectiveingredient to the coating material and subsequently drying in the samemanner as in the case of the coating film production.

Examples of the aforementioned solvent include water, chain having 1 tonot more than 5 carbon atoms (lower alcohols) and mixed solventsthereof, and water is particularly preferred.

The term “high hydrogen-bonding resin” refers to a resin having a highcontent of hydrogen-bonding group, and examples thereof include highhydrogen-bonding resins which satisfy a ratio of 5 to 60% in terms ofthe mass of the hydrogen-bonding group per unit resin mass. Examples ofthe hydrogen-bonding group include hydroxyl group, amino group, thiolgroup, carboxyl group, sulfonic acid group and phosphate group. As thehigh hydrogen-bonding resin used in the aforementioned coating material,a resin having a high content of hydroxyl group is more suitable.Examples of the aforementioned high hydrogen-bonding resin includepolyvinyl alcohols and polysaccharides, and the high hydrogen-bondingresin is preferably a polyvinyl alcohol or sodium carboxymethylcellulose, more preferably a polyvinyl alcohol. The polyvinyl alcoholmay contain a derivative thereof. It is noted here that theaforementioned high hydrogen-bonding resin may be used in combination aslong as the amount thereof is within the range which does not impair thegas barrier properties.

The aforementioned polyvinyl alcohol refers to one which is generallyobtained by saponification of polyvinyl acetate and it encompassespartially saponified polyvinyl alcohols in which the acetate groupremains in an amount of several 10%, as well as completely saponifiedpolyvinyl alcohols in which the acetate group remains in an amount ofonly a few %. The saponification degree of the polyvinyl alcohol ispreferably 70 to 97 mol %. The average polymerization degree ispreferably 200 to 3,000, more preferably 600 to 2,400. As theaforementioned polyvinyl alcohol, two or more polyvinyl alcohols havingdifferent saponification degrees and average polymerization degrees maybe used in combination. For mixing of two or more polyvinyl alcohols,for example, there is a method in which a polyvinyl alcohol having a lowpolymerization grade is added and then a polyvinyl alcohol having a highpolymerization grade is mixed. Examples of the polyvinyl alcohol includevarious types of Poval (Kuraray Co., Ltd.) and Gohsenol (NipponSynthetic Chemical Industry Co., Ltd.).

The term “swelling clay” refers to a clay having a swelling property.More particularly, the term refers to, among those fine powdersubstances that exhibit viscosity and plasticity when containing anappropriate amount of water, a substance having a swelling property.

As the swelling clay, one which is negatively charged due to thecomposition balance of the metal salt species is preferred, and examplesthereof include smectites such as hydrated aluminum silicate havingthree-layer structure.

The term “negatively charged” refers to a condition in which theswelling clay has a cation exchange property, and the amount of thecharge is expressed in the cation exchange capacity (CEC). The unit ofcation exchange capacity is milligram equivalent/100 g (normally,expressed as “meq/100 g”) and generally expressed in the number ofequivalents corresponding to the molarity of monovalent ions.

Examples of the smectites include beidellite, nontronite, saponite,hectorite, sauconite, bentonite and aluminum magnesium silicate, andthese may be used individually or two or more thereof may be used incombination as appropriate. Among such smectites, aluminum magnesiumsilicate and a bentonite are preferred, and a bentonite is morepreferred. It is noted here that the aforementioned swelling clay may beused in combination as long as the amount thereof is within the rangewhich does not impair the gas barrier properties.

The term “solid formulation” refers to a formulation in a solid form,and examples thereof include tablets (including sublingual tablets andorally-disintegrating tablets), capsules (including soft capsules andmicrocapsules), granules, subtle granules, powders, balls, troches andfilms.

Examples of the method of coating the solid formulation include, incases where the solid formulation is in the form of a tablet, thosecoating methods using a coating pan or tablet coating machine; and incases where the solid formulation is in the form of granules or powder,those methods using a fluidized bed coating machine or tumblingfluidized coating machine.

The term “laminated structure” refers to a structure in which aplurality of layered structures are laminated, and the term “orientplanarly” means to arrange in parallel to the reference plane. That is,the term “a coating film in which the laminated structures of theswelling clay are oriented planarly and dispersed in a network fashion”refers to a coating film in which the bands of the swelling clay arelaminated in 10 to 100 layers to form laminated structures which arearranged in almost parallel to the transverse section of the coatingfilm (cross-section parallel to the coating film surface) and the bandsare dispersed in a network fashion in the coating film. In this case,not only the bands are oriented completely in parallel, but also theymay be oriented with undulations or in such a manner that the bands runsnear or far from other bands running in all directions.

Since the aforementioned coating material for a solid formulation canform a thin coating film which prevents permeation of oxygen and watervapor on the surface of the solid formulation, the coating material canimpart gas barrier properties equivalent or superior to those of apackaging material such as PTP sheet (oxygen permeability coefficient:less than 1×10⁻⁴ cm³.mm/cm²·24 hr·atm; water vapor permeability: lessthan 1×10⁻⁴ g·mm/cm²·24 hr·atm) to the solid formulation.

In the aforementioned coating material, the ratio of the area occupiedby the aforementioned planarly-oriented laminated structures is, withrespect to the area of the longitudinal section (cross-sectionperpendicular to the coating film surface) of the aforementioned coatingfilm, preferably not less than 30%, more preferably not less than 35%,still more preferably not less than 42%.

Further, in the aforementioned coating material, it is preferred thatthe mass ratio of the high hydrogen-bonding resin and the swelling claybe 4:6 to 6:4. When the mass ratio of the high hydrogen-bonding resinand the swelling clay is not higher than 3:7, the coating materialbecomes highly viscous, so that spraying thereof may become difficult.In this case, spraying may become possible by lowering the concentrationof the coating material. However, there may arise another problem suchas prolonged production time. Further, when the mass ratio of the highhydrogen-bonding resin and the swelling clay is not less than 7:3, gasbarrier properties equivalent or superior to those of a packagingmaterial such as PTP sheet may not be attained.

The term “sugar alcohol derivative-type surfactant” refers to asurfactant having a sugar alcohol skeleton in the molecule. Examples ofthe type of the sugar alcohol include mannitol, xylitol, maltitol,trehalose, inositol and sorbitol. Examples of surfactant having astructure in which a hydrophobic group is bound to the sugar alcohol viaan ester bond include sorbitan fatty acid esters, polyoxyalkylenesorbitan fatty acid esters, sucrose fatty acid esters, sorbit fatty acidesters, polyoxyalkylene sorbit fatty acid esters, polyglycerols,polyglycerol fatty acid esters, glycerol fatty acid esters andpolyoxyalkylene glycerol fatty acid esters.

As the sugar alcohol derivative-type surfactant used in theaforementioned coating material, a sorbitan fatty acid ester and asucrose fatty acid ester are preferred, and a sorbitan fatty acid esteris more preferred. Further, among sorbitan fatty acid esters, thosehaving a high ratio of monoester are preferred, and those having a HLB(Hydrophilic Lipophilic Balance) in the range of 4 to 10 are preferred.In addition, the acyl group constituting the hydrophobic group may beany of the saturated, unsaturated, straight or branched acyl groups, andit is preferred that the acyl group have 12 to 18 carbon atoms. Examplesof such sorbitan fatty acid esters include sorbitan monolaurate,sorbitan monopalmitate and sorbitan monoleate, and these may be suitablyused in the aforementioned coating material. It is noted here that theaforementioned sugar alcohol derivative-type surfactant may be used incombination as long as the amount thereof is within the range which doesnot impair the gas barrier properties.

When the aforementioned coating material comprises the sugar alcoholderivative-type surfactant, the mass ratio of the high hydrogen-bondingresin and the swelling clay is preferably 2:8 to 5:5, more preferably2:8 to 4:6, still more preferably 2:8 to 3:7. When the mass ratio of thehigh hydrogen-bonding resin and the swelling clay is not higher than1:9, the coating material becomes highly viscous, making the coatingoperation difficult. In this case, coating may become possible bylowering the concentration of the coating material with an addition of asolvent. However, there may arise another problem such as prolongedproduction time. Further, when the mass ratio of the highhydrogen-bonding resin and the swelling clay becomes not less than 6:4,gas barrier properties equivalent or superior to those of a packagingmaterial such as PTP sheet may not be attained.

Although the content of the aforementioned sugar alcohol derivative-typesurfactant varies depending on the ratio of the aforementioned highhydrogen-bonding resin and the aforementioned swelling clay, it ispreferably 7 to 35%, more preferably 10 to 30%, still more preferably 12to 24%. The term “the content of the sugar alcohol derivative-typesurfactant” refers to a ratio (%) of the sugar alcohol derivative-typesurfactant with respect to the entire mixture obtained by adding thesugar alcohol derivative-type surfactant to the high hydrogen-bondingresin and the swelling clay. By adding such sugar alcoholderivative-type surfactant, coating of the solid formulation becomeseasy and the gas barrier properties of the resulting coating film areimproved. However, depending on the mass ratio of the highhydrogen-bonding resin and the swelling clay, when the content of thesugar alcohol derivative-type surfactant becomes not higher than 6% ornot less than 36%, gas barrier properties equivalent or superior tothose of a packaging material such as PTP sheet may not be attained.

In the aforementioned coating material, a pharmacologically acceptableadditive may be added as long as the amount thereof is within the rangewhich does not impair the gas barrier properties. For example, by addinga sugar or sugar alcohol such as maltose, maltitol, sorbitol, xylitol,fructose, glucose, lactitol, isomaltose, lactose, erythritol, mannitol,trehalose or sucrose, croscarmellose sodium or low-substitutedhydroxypropyl cellulose as a swelling property-disintegrating agent, thedisintegration property of the coating film can be improved, and byadding triethyl citrate, polyethylene glycol or glycerin as aplasticizer, the strength of the coating film can be improved.

Also, an additive which is conventionally used in film-coating by thoseskilled in the art may be further added to the aforementioned coatingmaterial. Examples of such additive include coloring agents such asplant-extract dyes and masking agents such as titanium oxide, calciumcarbonate and silicon dioxide.

The solid formulation is characterized by being coated with theaforementioned coating material.

Examples of the aforementioned solid formulation include tablets(including sublingual tablets and orally-disintegrating tablets),capsules (including soft capsules and microcapsules), granules, subtlegranules, powders, balls, troches and films.

The aforementioned solid formulation may be one which has a coating filmof the aforementioned coating material on the surface thereof havinganother coating film made of a gastric-soluble or enteric-solublemacromolecular substance or the like, or one which has another coatingfilm made of a gastric-soluble or enteric-soluble macromolecularsubstance or the like on the surface thereof having a coating film ofthe aforementioned coating material.

EXAMPLES

The coating and material will now be concretely described by way ofexamples thereof. However, the disclosure is not restricted thereto.

The dispersion condition of the swelling clay, oxygen permeabilitycoefficient and water vapor permeability were measured by using acoating film (film) obtained from the coating material.

Method of Evaluating the Dispersion Condition of the Swelling Clay

In accordance with a focused ion beam method, the coating film was madethin by a gadolinium ion beam (FB-2000A; Hitachi High-Tech Manufacturing& Service Corporation). The thus obtained thin coating film was observedunder a transmission electron microscope (H-9000UHR; Hitachi High-TechManufacturing & Service Corporation) to visually measure the number oflaminated layers of the swelling clay.

When the swelling clay is oriented planarly to the transverse section ofthe coating film (cross-section parallel to the coating film surface), afocused and clear micrograph is obtained, so that a single layer of theswelling clay (thickness of about 1 nm) and a laminated structurethereof can be observed. On the other hand, when the swelling clay isnot oriented planarly, an unfocused and fuzzy micrograph is obtained.Therefore, the ratio of the laminated structure of the swelling clayoriented planarly to the transverse section of the coating film wascalculated by dividing the area of the focused micrograph of thelaminated structure by the area of the observation region (2.5 μm×2.5 μmsquare). The area was expressed in a numerical value by performing imageanalysis with NIHimage.

Method of Measuring the Oxygen Permeability Coefficient

In accordance with a standard specification in the art, JIS K7126-1(2006) (Gas Permeability Test Method by Gas Chromatography), the oxygenpermeability coefficient was measured at a temperature of 23±2° C. inrelative humidities of 0% (0% RH) and 90% (90% RH) by using an oxygenpermeability coefficient measuring apparatus (GTR-30XAD2 and G2700T·F;GTR Tec Corporation). Hereinafter, relative humidity is abbreviated as“RH.” Method of measuring the water vapor permeability

A standard specification in the art, JIS K8123 (1994), was partiallymodified to measure the water vapor permeability. First, a coating filmprepared by the method described below was held up to the light and acircular piece having a diameter of 3.5 cm was excised from a portion ofthe coating film having no pinhole and uniform thickness. The thicknessof the coating film was measured at 5 arbitrary spots. Next, 3 g ofcalcium chloride (particle size of 850 to 2,000 μm) was placed in analuminum cup (diameter of 30 mm), and the thus excised circular coatingfilm and a film-fixing ring were placed in the order mentioned onto thealuminum cup. The ring was fixed by placing a weight thereon. In thiscondition, molten paraffin wax was poured into the margin of thealuminum cup. After the paraffin wax was solidified, the weight wasremoved and the mass of the entire aluminum cup was measured as theinitial mass. Then, the aluminum cup was placed in a thermostat bath at40° C. and 75% RH. The aluminum cup was removed every 24 hours tomeasure the mass thereof, and the water vapor permeability wascalculated using the following equation. It should be noted here that,in all of the below-described tests for measuring the water vaporpermeability, the following applied: r=1.5 cm, t=24 hours and C=1 atm.

-   -   Water vapor permeability P (g·mm/cm²·24 hr·atm)=W·A/B·t·C    -   W: Increased mass in 24 hours (g)    -   A: Average thickness of the coating film at 5 spots (mm)    -   B: Permeation area πr² (cm²)    -   t: Elapsed time (hr)    -   C: Atmospheric pressure (atm)

Reference Example 1 Preparation of a Polyvinyl Alcohol-Based CoatingFilm

To 42.5 parts by mass of water, 7.5 parts by mass of OPADRY II HP(registered trademark) (Colorcon Japan) was added, and the resultingmixture was stirred to obtain a dispersion. Then, the thus obtaineddispersion was poured into a polypropylene tray having a flat bottom anddried overnight in a 50° C. oven in a leveled condition to obtain acoating film. This coating film was a polyvinyl alcohol (PVA)-basedcoating film. Hereinafter, polyvinyl alcohol is abbreviated as “PVA.”

Reference Example 2 Preparation of a Modified PVA-Based Coating Film

To 45.0 parts by mass of water, 3.5 parts by mass of POVACOAT(registered trademark) (Nisshin Kasei Co., Ltd.), 1.0 parts by mass oftitanium oxide and 0.5 parts by mass of talc were added, and theresulting mixture was stirred to obtain a dispersion. A coating film wasthen obtained in the same manner as in Reference Example 1. This coatingfilm was a modified PVA-based coating film.

Reference Example 3 Preparation of a Sodium CarboxymethylCellulose-Based Coating Film

To 46.5 parts by mass of water, 3.5 parts by mass of OPAGLOS2(registered trademark) (Colorcon Japan) was added, and the resultingmixture was stirred to obtain a dispersion. A coating film was obtainedin the same manner as in Reference Example 1. This coating film was asodium carboxymethyl cellulose (CMC)-based coating film. Hereinafter,sodium carboxymethyl cellulose is abbreviated as “CMC.”

Table 1 shows the results of the measurements of the oxygen permeabilitycoefficient and the water vapor permeability of the coating films ofReference Examples 1 to 3 used for coating solid formulations.

TABLE 1 Reference Reference Example 2 Reference PTP packaging Example 1(modified PVA- Example 3 material (moisture- (PVA-based based coating(CMC-based resistant PTP) coating film) film) coating film) Oxygenpermeability 23° C., 0% RH No Data 1.5 × 10⁻² No Data 3.0 × 10⁻⁶coefficient 23° C., 90% RH 4.0 × 10⁻⁵ 4.4 × 10  3.6 × 10⁻⁴ 2.6 × 10⁻⁴(cm³ · mm/cm² · 24 hr · atm) Water vapor 40° C., 75% RH 3.3 × 10⁻⁵ 3.1 ×10⁻³ 6.1 × 10⁻⁴ 5.3 × 10⁻³ permeability (g · mm/cm² · 24 hr · atm)

From Table 1, it became apparent that only the PTP packaging materialhad both the oxygen permeability coefficient and the water vaporpermeability at less than 1×10⁻⁴ and that the gas barrier properties ofthe coating films of Reference Examples 1 to 3 used for coating solidformulations were markedly inferior compared to those of the PTPpackaging material.

Example 1

To 42.55 parts by mass of water, 1.2 parts by mass of PVA (EG-05; NipponSynthetic Chemical Industry Co., Ltd.) and 56.25 parts by mass of 3.2%bentonite solution were added, and the resulting mixture was stirredusing a homogenizer (Polytron Model KR) to obtain a dispersion. The 3.2%bentonite solution was prepared by adding 32 parts by mass of bentonite(Kunipia-F; Kunimine Industries Co., Ltd.) (cation exchange capacity:115 meq/100 g) to 968 parts by mass of stirred water; uniformlydispersing the resulting mixture using a homogenizer; and thensuction-filtrating the resultant through a filter paper. Hereinafter,bentonite is abbreviated as “BT.”

The thus obtained dispersion was sprayed onto the back side of thepolypropylene balance tray and immediately dried with hot air using adryer. After repeating several rounds of the spraying and dryer drying,the balance tray was altogether placed in a 50° C. oven and driedovernight. Subsequently, a coating film was separated from the balancetray to obtain the coating film of Example 1.

Example 2

To 137.0 parts by mass of water, 2.64 parts by mass of PVA (EG-05;Nippon Synthetic Chemical Industry Co., Ltd.), 192.5 parts by mass of3.2% BT solution and 1.2 parts by mass of sorbitan monolaurate (Span20;Wako Pure Chemical Industries, Ltd.) were added, and the resultingmixture was stirred using the homogenizer (Polytron Model KR) to obtaina dispersion. From this dispersion, the coating film of Example 2 wasobtained in accordance with the method of Example 1.

Comparative Example 1

To 42.55 parts by mass of water, 1.2 parts by mass ofhydroxypropylmethyl cellulose (TC-5W; Shin-Etsu Chemical Co., Ltd.) and56.25 parts by mass of 3.2% BT solution were added, and the resultingmixture was stirred using the homogenizer (Polytron Model KR) to obtaina dispersion. From this dispersion, the coating film of ComparativeExample 1 was obtained in accordance with the method of Example 1.Hereinafter, hydroxypropylmethyl cellulose is abbreviated as “HPMC.”

Comparative Example 2

To 96.4 parts by mass of water, 10.0 parts by mass of PVA was added, andthe resulting mixture was stirred using a stirrer to obtain adispersion. From this dispersion, the coating film of ComparativeExample 2 was obtained in accordance with the method of Example 1.

Comparative Example 3

To 56.7 parts by mass of water, 2.64 parts by mass of PVA, 6.16 parts bymass of talc and 1.2 parts by mass of sorbitan monolaurate were added,and the resulting mixture was stirred using the homogenizer to obtain adispersion. From this dispersion, the coating film of ComparativeExample 3 was obtained in accordance with the method of Example 1.

Table 2 shows the results of the measurements of the oxygen permeabilitycoefficient and the water vapor permeability of the coating filmsobtained in Examples 1 and 2 and Comparative Examples 1 to 3.

TABLE 2 Comparative Comparative Comparative Example 1 Example 2 Example1 Example 2 Example 3 PVA or HPMC/BT or 4/6/0 26.4/61.6/12 4/6/0 10/0/026.4/61.6/12 talc/sorbitan monolaurate (mass ratio) Oxygen permeability23° C., 90% RH 7.0 × 10⁻⁶ 3.2 × 10⁻⁶ No Data 5.7 × 10⁻⁵ No Datacoefficient (cm³ · mm/cm² · 24 hr · atm) Water vapor 40° C., 75% RH 3.4× 10⁻⁵ 1.9 × 10⁻⁵ 3.9 × 10⁻⁴ 9.1 × 10⁻⁴ 1.1 × 10⁻³ permeabilitycoefficient (g · mm/cm² · 24 hr · atm)

As a result, it was revealed that, compared to HPMC, PVA, that is, ahigh hydrogen-bonding resin, exhibited more prominent effect to decreasethe oxygen permeability coefficient and the water vapor permeability ofthe coating film (comparison between Example 1 and Comparative Example1). In addition, when BT, that is, a swelling clay, was contained in thecoating film, the oxygen permeability coefficient and the water vaporpermeability of the coating film were both markedly decreased(comparison between Example 1 and Comparative Example 2), and thiseffect was more prominent compared to the case in which talc was used inplace of BT (comparison between Example 2 and Comparative Example 3).From these results, it was revealed that the coating film of Example 1comprising PVA and BT at a particular ratio and the coating film ofExample 2 comprising PVA, BT and sorbitan monolaurate at a particularratio had both the oxygen permeability coefficient and the water vaporpermeability at less than 1×10⁻⁴ and that, therefore, these coatingfilms had gas barrier properties equivalent or superior to those of thePTP packaging material.

Measurement of the Coating Films Under a Transmission ElectronMicroscope

Using a focused ion beam method, the longitudinal section of the coatingfilms of Examples 1 and 2 were observed under a transmission electronmicroscope. FIGS. 1 and 2 show micrographs of Examples 1 and 2,respectively.

Example 3

To 51.6 parts by mass of water, 1.5 parts by mass of PVA and 46.9 partsby mass of 3.2% BT solution were added, and the coating film of Example3 was obtained in accordance with the method of Example 1. Using afocused ion beam method, the longitudinal section of the coating film ofExample 3 was observed under a transmission electron microscope. Themicrograph thereof is shown in FIG. 3.

Comparative Example 4

To 33.5 parts by mass of water, 0.9 parts by mass of PVA and 65.6 partsby mass of 3.2% BT solution were added, and the coating film ofComparative Example 4 was obtained in accordance with the method ofExample 1. The cross section of the coating film was observed inaccordance with the method of Example 3. The micrograph thereof is shownin FIG. 4.

Comparative Example 5

To 89.9 parts by mass of water, 2.25 parts by mass of PVA and 7.8 partsby mass of 3.2% BT solution were added, and the coating film ofComparative Example 5 was obtained in accordance with the method ofExample 1. The cross section of the coating film was observed inaccordance with the method of Example 3. The micrograph thereof is shownin FIG. 5.

Table 3 shows the dispersion condition of BT, as well as the oxygenpermeability coefficient and the water vapor permeability of the coatingfilms obtained in Examples 1 to 3 and Comparative Examples 4 and 5.

TABLE 3 Comparative Comparative Example 1 Example 2 Example 3 Example 4Example 5 PVA/BT/sorbitan 4/6/0 26.4/61.6/12 5/5/0 3/7/0 9/1/0monolaurate Ratio of the planarly- 51 42 53 20 4 oriented BT laminatedstructures (%) Network structures of BT present present present presentnot present Oxygen permeability 7.0 × 10⁻⁶ 3.2 × 10⁻⁶ 2.6 × 10⁻⁵ 8.3 ×10⁻³ No Data coefficient (cm³ · mm/cm² · 24 hr · atm) Water vaporpermeability 3.4 × 10⁻⁵ 1.9 × 10⁻⁵ 2.5 × 10⁻⁵ 5.2 × 10⁻⁵ 2.3 × 10⁻⁴ (g ·mm/cm² · 24 hr · atm)

As a result, it was revealed that gas barrier properties equivalent orsuperior to those of the PTP packaging material can be attained when theratio of the BT laminated structures oriented planarly to the transversesection of the coating film is not less than 30%.

Example 4

Following the constitution shown in Table 4, water, PVA and BT solutionwere mixed, and a coating film was obtained in accordance with themethod of Example 1. The oxygen permeability coefficient (23° C., 90%RH) and the water vapor permeability (40° C., 75% RH) were measured.

Comparative Example 6

Following the constitution shown in Table 4, water, PVA and BT solutionwere mixed, and a dispersion was obtained in accordance with the methodof Example 1. A coating film was then obtained by the method of Example1, and the oxygen permeability coefficient (23° C., 90% RH) and thewater vapor permeability (40° C., 75% RH) were measured.

Table 4 shows the effects of the mass ratio of PVA and BT (PVA/BT) onthe oxygen permeability coefficient and the water vapor permeability.

TABLE 4 Oxygen permeability Water vapor coefficient permeability PVA/(cm³ · mm/ (g · mm/ BT cm² · 24 hr · atm) cm² · 24 hr · atm) Example 14/6 7.0 × 10⁻⁶ 3.4 × 10⁻⁵ Example 3 5/5 2.6 × 10⁻⁵ 2.5 × 10⁻⁵ Example 46/4 1.6 × 10⁻⁵ 3.2 × 10⁻⁵ Comparative Example 4 3/7 8.3 × 10⁻³ 5.2 ×10⁻⁵ Comparative Example 6 7/3 No Data 1.6 × 10⁻⁴

As a result, it was revealed that, when the mass ratio of PVA and BT(PVA/BT) is 4:6 to 6:4 (4/6 to 6/4), the oxygen permeability coefficientand the water vapor permeability both becomes less than 1×10⁻⁴ and that,therefore, gas barrier properties equivalent or superior to those of thePTP packaging material can be attained.

Examples 5 to 7 and Comparative Examples 7 to 9

Water, PVA, BT solution and respective surfactant were mixed and adispersion was obtained in accordance with the method of Example 2. Acoating film was then obtained by the method of Example 1, and theoxygen permeability coefficient (23° C., 90% RH) and the water vaporpermeability (40° C., 75% RH) were measured.

Table 5 shows the effects of the type of the surfactant on the oxygenpermeability coefficient and the water vapor permeability. Theevaluations were carried out by fixing the mass ratio of PVA, BT and therespective surfactant at 26.4:61.6:12 (26.4/61.6/12).

TABLE 5 Oxygen permeability Water vapor coefficient permeability (cm³ ·mm/ (g · mm/ Surfactant cm² · 24 hr · atm) cm² · 24 hr · atm) Example 2Sorbitan 3.2 × 10⁻⁶ 1.9 × 10⁻⁵ monolaurate Example 5 Sorbitan 1.6 × 10⁻⁵6.0 × 10⁻⁵ monopalmitate Example 6 Sorbitan monoleate 2.2 × 10⁻⁵ 2.9 ×10⁻⁵ Example 7 Sucrose stearate 1.4 × 10⁻⁵ 1.9 × 10⁻⁵ Comparative Nosurfactant 8.3 × 10⁻³ 5.2 × 10⁻⁵ Example 7 Comparative Pluronic 7.3 ×10⁻⁴ 1.9 × 10⁻⁵ Example 8 Comparative Polyoxyethylene 4.4 × 10⁻² 4.7 ×10⁻⁵ Example 9 hydrogenated castor oil

As a result, it was revealed that, in addition to the addition ofsorbitan monolaurate, the addition of sorbitan monopalmitate, sorbitanmonooleate or sucrose stearate makes both of the oxygen permeabilitycoefficient and the water vapor permeability to become less than 1×10⁻⁴and that, therefore, gas barrier properties equivalent or superior tothose of the PTP packaging material can be attained. This suggests thatthe sugar alcohol derivative-type surfactants contribute to animprovement of gas barrier properties.

Examples 8 to 10

Following the constitution shown in Table 6, water, PVA, BT solution andsorbitan monolaurate were mixed, and a dispersion was obtained inaccordance with the method of Example 1. A coating film was thenobtained by the method of Example 1, and the oxygen permeabilitycoefficient (23° C., 90% RH) and the water vapor permeability (40° C.,75% RH) were measured.

Comparative Examples 10 and 11

Following the constitution shown in Table 6, water, PVA, BT solution andsorbitan monolaurate were mixed, and a dispersion was obtained inaccordance with the method of Example 2. A coating film was thenobtained by the method of Example 1, and the oxygen permeabilitycoefficient (23° C., 90% RH) and the water vapor permeability (40° C.,75% RH) were measured.

Table 6 shows the effects of the mass ratio of PVA and BT (PVA/BT) onthe oxygen permeability coefficient and the water vapor permeability.The content of sorbitan monolaurate was set at 12% in all of the cases.

TABLE 6 Oxygen permeability Water vapor PVA/BT/ coefficient permeabilitysorbitan PVA/ (cm³ · mm/ (g · mm/ monolaurate BT cm² · 24 hr · atm) cm²· 24 hr · atm) Example 8 17.6/70.4/12 2/8 3.8 × 10⁻⁵ 5.0 × 10⁻⁵ Example9 35.2/52.8/12 4/6 3.9 × 10⁻⁵ 5.7 × 10⁻⁵ Example 10 44/44/12 5/5 5.4 ×10⁻⁵ 2.5 × 10⁻⁵ Comparative 52.8/35.2/12 6/4 1.1 × 10⁻² 4.2 × 10⁻⁵Example 10 Comparative 52.8/35.2/12 1/9 1.9 × 10⁻⁵ 1.9 × 10⁻⁴ Example 11

As a result, it was revealed that, when the mass ratio of PVA and BT(PVA/BT) is 2:8 to 5:5 (2/8 to 5/5), the addition of sorbitanmonolaurate makes both of the oxygen permeability coefficient and thewater vapor permeability to become less than 1×10⁻⁴ and that, therefore,gas barrier properties equivalent or superior to those of the PTPpackaging material can be attained.

Examples 11 and 12 and Comparative Example 12

Following the constitution shown in Table 7, water, PVA, BT solution andsorbitan monolaurate were mixed, and a dispersion was obtained inaccordance with the method of Example 2. A coating film was thenobtained by the method of Example 1, and the oxygen permeabilitycoefficient (23° C., 90% RH) and the water vapor permeability (40° C.,75% RH) were measured.

Table 7 shows the effects of the sorbitan monolaurate content on theoxygen permeability coefficient and the water vapor permeability. Theevaluations were carried out by fixing the mass ratio of PVA and BT(PVA/BT) at 5:5 (5/5).

TABLE 7 Oxygen permeability Water vapor PVA/BT/ coefficient permeabilitysorbitan PVA/ (cm³ · mm/ (g · mm/ monolaurate BT cm² · 24 hr · atm) cm²· 24 hr · atm) Example 3 50/50/0 5/5 2.6 × 10⁻⁵ 2.5 × 10⁻⁵ Example 1044/44/12 5/5 5.4 × 10⁻⁵ 3.4 × 10⁻⁵ Example 11 47/47/6 5/5 1.4 × 10⁻⁵ 3.1× 10⁻⁵ Example 12 38/38/24 5/5 5.3 × 10⁻⁵ 5.6 × 10⁻⁵ Comparative32/32/36 5/5 8.7 × 10⁻⁵ 1.2 × 10⁻⁴ Example 12

As a result, it was revealed that, when PVA/BT=5/5, the sorbitanmonolaurate content in the range of 0 to 24% makes both of the oxygenpermeability coefficient and the water vapor permeability to be lessthan 1×10⁻⁴ and that, therefore, gas barrier properties equivalent orsuperior to those of the PTP packaging material can be attained.

Examples 13 and 14 and Comparative Examples 13 and 14

Following the constitution shown in Table 8, water, PVA, BT solution andsorbitan monolaurate were mixed, and a dispersion was obtained inaccordance with the method of Example 2. A coating film was thenobtained by the method of Example 1, and the oxygen permeabilitycoefficient (23° C., 90% RH) and the water vapor permeability (40° C.,75% RH) were measured.

Table 8 shows the effects of the sorbitan monolaurate content on theoxygen permeability coefficient and the water vapor permeability. Theevaluations were carried out by fixing the mass ratio of PVA and BT(PVA/BT) at 2:8 (2/8).

TABLE 8 Oxygen permeability Water vapor PVA/BT/ coefficient permeabilitysorbitan PVA/ (cm³ · mm/ (g · mm/ monolaurate BT cm² · 24 hr · atm) cm²· 24 hr · atm) Example 8 17.6/70.4/12 2/8 3.8 × 10⁻⁵ 5.0 × 10⁻⁵ Example13 15.2/60.8/24 2/8 No Data 6.9 × 10⁻⁵ Example 14 12.8/51.2/36 2/8 8.1 ×10⁻⁵ 7.9 × 10⁻⁵ Comparative 18.8/75.2/6 2/8 2.7 × 10⁻³ 5.0 × 10⁻⁵Example 13 Comparative 10.4/41.6/48 2/8 No Data 1.0 × 10⁻⁴ Example 14

As a result, it was revealed that, when PVA/BT=2/8, the sorbitanmonolaurate content in the range of 12 to 36% makes both of the oxygenpermeability coefficient and the water vapor permeability to be lessthan 1×10⁻⁴ and that, therefore, gas barrier properties equivalent orsuperior to those of the PTP packaging material can be attained.

Comparative Example 15 Production of an Ascorbic Acid-Containing Tablet

To evaluate the barrier properties against oxygen and water vapor, anascorbic acid-containing tablet which is unstable against oxygen andwater vapor was produced.

First, lactose, crystalline cellulose and hydroxypropyl cellulose-SLwere loaded into a vertical granulator and granulated with water inwhich cupric sulfate pentahydrate had been dissolved. The thus obtainedgranules were dried overnight at 50° C. and pulverized using a comil toobtain granules A. Then, the granules A and ascorbic acid were loadedinto a vertical granulator and after granulation with ethanol, theresultant was dried at 50° C. for 2 hours and pulverized using a comilto obtain granules B. Subsequently, the granules B, a low-substitutedhydroxypropyl cellulose, croscarmellose sodium and magnesium stearatewere mixed, and the resultant was tableted using a rotary tabletingmachine (Kikusui Chemical Industries Co., Ltd.) to obtain an ascorbicacid-containing tablet (diameter of 8 mm, 12R). The thus obtainedascorbic acid-containing tablet not coated with a coating material wasused as Comparative Example 15.

Example 15

Production of an Ascorbic Acid-Containing Coated Tablet Coated with theDispersion of Example 2

To a coating pan (Hi-Coater mini; Freund Corporation), 400 g of theascorbic acid tablet of Comparative Example 15 was loaded, and thedispersion prepared in Example 2 was used as the coating material tocoat the ascorbic acid-containing tablet. The coating with the coatingmaterial was performed to a coating thickness of 60 μm to obtain anascorbic acid-containing coated tablet. The thus obtained ascorbicacid-containing coated tablet coated with the dispersion of Example 2was used as Example 15.

Comparative Example 16

Production of an Ascorbic Acid-Containing Coated Tablet Coated with theDispersion of Reference Example 3

To the coating pan (Hi-Coater mini; Freund Corporation), 400 g of theascorbic acid tablet of Comparative Example 15 was loaded, and thedispersion prepared in Reference Example 3 was used as the coatingmaterial to coat the tablet. The coating with the coating material wasperformed to a coating thickness of 60 μm. The thus obtained ascorbicacid-containing coated tablet coated with the dispersion of ReferenceExample 3 was used as Comparative Example 16.

The Disintegration Property of the Ascorbic Acid-Containing CoatedTablet

The disintegration property of the ascorbic acid-containing coatedtablet of Example 15 was evaluated using an elution tester. That is, oneascorbic acid-containing coated tablet was placed in 900 mL of waterwhich had been heated to 37° C., and the time required for the coatingfilm to start to detach from the tablet surface was measured. As theresult, the time required for the coating film to start to detach fromthe tablet surface was about 2 minutes. Consequently, it was revealedthat the ascorbic acid-containing coated tablet of Example 15 hasexcellent disintegration property, and it was suggested that thedispersion of Example 2 may be applied in coating not only sustainedrelease formulations, but also immediate release formulations.

The storage stability of the ascorbic acid-containing coated tablets

The ascorbic acid-containing tablet of Comparative Example 15 and theascorbic acid-containing coated tablets of Example 15 and ComparativeExample 16 were stored for 4 weeks in an open condition or an airtightcondition in a desiccator at 25° C. and 95% RH to evaluate the residualratio of ascorbic acid (drug residual ratio) with time. The term “in anopen condition” means to place each tablet as is in the desiccator, andthe term “in an airtight condition” means to put each tablet into aglass bottle having a plastic inner lid and outer lid, which bottle isthen sealed, and place the glass bottle in the desiccator whilemaintaining the sealed condition.

FIG. 6 is a graph showing the changes with time in the drug residualratio. In FIG. 6, the open triangle (Δ), filled triangle (▴), opensquare (□), filled square (▪), open circle (∘) and filled circle ()represent the results of: the ascorbic acid-containing coated tablet ofExample 15 placed in an airtight condition; the ascorbic acid-containingcoated tablet of Example 15 in an open condition; the ascorbicacid-containing coated tablet of Comparative Example 16 placed in anairtight condition; the ascorbic acid-containing coated tablet ofComparative Example 16 placed in an open condition; the ascorbicacid-containing tablet of Comparative Example 15 placed in an airtightcondition; and the ascorbic acid-containing tablet of ComparativeExample 15 placed in an open condition, respectively. In addition, theordinate and the abscissa indicate the drug residual ratio (%) and thestorage period (W), respectively, and the W means weeks.

In the ascorbic acid-containing tablet of Comparative Example 15 and theascorbic acid-containing coated tablet of Comparative Example 16 in anopen condition, the drug residual ratio decreased with time. However, inthe ascorbic acid-containing coated tablet of Example 15 in an opencondition, degradation of the drug was not observed even after the4-week storage and the stability was maintained at a level equivalent tothe case where the tablet was placed in an airtight condition.Accordingly, it was revealed that the ascorbic acid-containing coatedtablet of Example 15 has high barrier properties against oxygen andwater vapor.

Comparative Example 17 Production of a Propantheline Bromide-ContainingTablet

To evaluate gas barrier properties, a propantheline bromide-containingtablet known to be extremely unstable in unpacked condition wasproduced. A propantheline bromide-containing tablet (Methaphyllin(registered trademark); Eisai Co., Ltd.) was pulverized using a mortarin a dry box to prevent moisture absorption, and the thus obtainedgranules of the pulverized tablet were again tableted using a rotarytableting machine (Kikusui Chemical Industries Co., Ltd.) to obtain apropantheline bromide-containing tablet (diameter of 8 mm, 12R). Thethus obtained propantheline bromide-containing tablet not coated with acoating material was used as Comparative Example 17.

Example 16

Production of a Propantheline Bromide-Containing Coated Tablet Coatedwith the Dispersion of Example 2

To the coating pan (Hi-Coater mini; Freund Corporation), 400 g of thepropantheline bromide-containing tablet of Comparative Example 17 wasloaded, and the dispersion prepared in Example 2 was used as the coatingmaterial to coat the propantheline bromide-containing tablet. Thecoating with the coating material was performed to a coating thicknessof 60 μm to obtain a propantheline bromide-containing coated tablet. Thethus obtained propantheline bromide-containing coated tablet was used asExample 16.

Comparative Example 18

Production of a Propantheline Bromide-Containing Coated Tablet Coatedwith a Commercially-Available General-Purpose Coating FormulationSolution

To distilled water, a mixture of hydroxypropylmethyl cellulose 2910,titanium oxide and Macrogol 400 (Opadry OY-7300(registered trademark);Colorcon Japan) was added and dissolved to obtain acommercially-available general-purpose coating formulation solution. Tothe coating pan (Hi-Coater mini; Freund Corporation), 400 g of thepropantheline bromide-containing tablet of Comparative Example 17 wasloaded, and the commercially-available general-purpose coatingformulation solution was used as the coating material to coat thetablet. The coating with the coating material was performed to a coatingthickness of 60 μm. The thus obtained propantheline bromide-containingcoated tablet was used as Comparative Example 18.

Comparative Example 19

Production of a Propantheline Bromide-Containing Coated Tablet Coatedwith a Commercially-Available Moisture-Resistant Formulation Solution

Sodium lauryl sulfate (15 g) was added to distilled water (875 g) andthe resultant was stirred until the sodium lauryl sulfate was completelydissolved. Next, aminoalkyl methacrylate copolymer E (Eudragit EPO(registered trademark); Degusssa Co.) (100 g) was added and stirred, andwhen it was uniformly dispersed, stearic acid (10 g) was added. Theresultant was further stirred to obtain a commercially-availablemoisture-resistant formulation solution. To the coating pan (Hi-Coatermini; Freund Corporation), 400 g of the propantheline bromide-containingtablet of Comparative Example 17 was loaded, and thecommercially-available moisture-resistant coating formulation solutionwas used as the coating material to coat the tablet. The coating withthe coating material was performed to a coating thickness of 60 μm. Thethus obtained propantheline bromide-containing coated tablet was used asComparative Example 19.

Comparative Example 20 Propantheline Bromide Sugar-Coated Tablet

A propantheline bromide tablet (Pro-Banthine (registered trademark);Pfizer Inc.) as is, was used as the propantheline bromide sugar-coatedtablet of Comparative Example 20.

The Storage Stability of the Propantheline Bromide-Containing CoatedTablets and the Propantheline Bromide Sugar-Coated Tablet

The propantheline bromide-containing tablet of Comparative Example 17,the propantheline bromide-containing coated tablets of Example 16 andComparative Examples 18 and 19, and the propantheline bromidesugar-coated tablet of Comparative Example 20 were each stored for 2months in an open condition in a desiccator at 30° C. and 75% RH toevaluate the residual ratio of propantheline bromide (drug residualratio) with time. The term “in an open condition” means to put eachtablet in a glass bottle and place the glass bottle as is without anycovering in the desiccator.

FIG. 7 is a graph showing the changes with time in the residual ratio ofpropantheline bromide (drug residual ratio). In FIG. 7, the open circle(∘), filled circle (), filled square (▪), filled triangle (▴) and opentriangle (Δ) represent the results of: the propanthelinebromide-containing coated tablet of Example 16; the propanthelinebromide-containing tablet of Comparative Example 17; the propanthelinebromide-containing coated tablet of Comparative Example 18; thepropantheline bromide-containing coated tablet of Comparative Example19; and the propantheline bromide sugar-coated tablet of ComparativeExample 20, respectively. In addition, the ordinate and the abscissaindicate the drug residual ratio (%) and the storage period (W),respectively, and the W means weeks.

As a result, in the propantheline bromide-containing tablet ofComparative Example 17, as well as in the propanthelinebromide-containing coated tablets of Comparative Example 18 andComparative Example 19, the drug residual ratio markedly decreasedduring the 4-week storage in an open condition. However, in thepropantheline bromide-containing coated tablet of Example 16 and thepropantheline bromide sugar-coated tablet of Comparative Example 20,degradation of the drug was not observed even after the 4-week storagein an open condition.

In addition, in the propantheline bromide-containing coated tablet ofExample 16 and the propantheline bromide sugar-coated tablet ofComparative Example 20, when they were stored in an open condition for 8weeks, a minor decrease in their drug residual ratio was observed.However, there was no significant difference in their drug residualratios. Therefore, it was revealed that the propanthelinebromide-containing coated tablet of Example 16 has high barrierproperties at a level equivalent to the propantheline bromidesugar-coated tablet.

Furthermore, in the propantheline bromide sugar-coated tablet ofComparative Example 20, when it was stored in an open condition for 8weeks, there was confirmed an adhesion to the wall of the glass bottleand between the propantheline bromide sugar-coated tablets caused bymelting of the sugar coat and a deterioration in the quality wasobserved. However, in the propantheline bromide-containing coatedtablets of Example 16, such an adhesion to the wall of the glass bottleand between the propantheline bromide-containing coated tablet was notobserved at all. Therefore, it was revealed that the propanthelinebromide-containing coated tablet of Example 16, in an open condition at30° C. and 75% RH, has a superior apparent stability compared to thepropantheline bromide sugar-coated tablet of Comparative Example 20.

From the above Examples, it was demonstrated that the gas barriercoating material is useful as a versatile coating material for solidformulations, especially as a coating film of solid formulations whichcontain a drug unstable against oxygen and/or water vapor.

INDUSTRIAL APPLICABILITY

The coating material is useful as a coating material for solidformulations, especially as a coating film of solid formulations whichcontain a drug unstable against oxygen and/or water vapor and ourmethods are useful in coating solid formulations.

What is claimed is:
 1. A method of improving stability of drugs in asolid pharmaceutical formulation against oxygen and water vaporcomprising coating the solid pharmaceutical formulation with a coatingmaterial including a high hydrogen-bonding resin and a swelling clay. 2.The method according to claim 1, which forms a coating film in whichlaminated structures of said swelling clay are oriented planarly anddispersed in a network fashion.
 3. The method according to claim 2,wherein a ratio of an area occupied by said planarly-oriented laminatedstructures is not less than 30% with respect to an area of thelongitudinal section of said coating film.
 4. The method according toclaim 1, wherein a mass ratio of said high hydrogen-bonding resin andsaid swelling clay is 4:6 to 6:4.
 5. The method according to claim 1,wherein said coating material comprises a sugar alcohol derivativesurfactant.
 6. A method of improving gas barrier properties of a solidpharmaceutical formulation against oxygen and water vapor comprisingcoating the solid pharmaceutical formulation with a coating materialincluding a high hydrogen-bonding resin and a swelling clay.
 7. Themethod according to claim 6, which forms a coating film in whichlaminated structures of said swelling clay are oriented planarly anddispersed in a network fashion.
 8. The method according to claim 7,wherein a ratio of an area occupied by said planarly-oriented laminatedstructures is not less than 30% with respect to an area of thelongitudinal section of said coating film.
 9. The method according toclaim 6, wherein a mass ratio of said high hydrogen-bonding resin andsaid swelling clay is 4:6 to 6:4.
 10. The method according to claim 6,wherein said coating material comprises a sugar alcohol derivativesurfactant.
 11. A method according of film-coating a solidpharmaceutical formulation comprising applying a coating materialincluding a high hydrogen-bonding resin in a swelling clay to the solidpharmaceutical formulation.
 12. The method to claim 11, which forms acoating film in which laminated structures of said swelling clay areoriented planarly and dispersed in a network fashion.
 13. The methodaccording to claim 12, wherein a ratio of an area occupied by saidplanarly-oriented laminated structures is not less than 30% with respectto an area of the longitudinal section of said coating film.
 14. Themethod according to claim 11, wherein a mass ratio of said highhydrogen-bonding resin and said swelling clay is 4:6 to 6:4.
 15. Themethod according to claim 11, wherein said coating material comprises asugar alcohol derivative surfactant.
 16. A method of manufacturing asolid pharmaceutical formulation comprising coating the solidpharmaceutical formulation with a coating material including a highhydrogen-bonding resin and a swelling clay.
 17. The method according toclaim 16, which forms a coating film in which laminated structures ofsaid swelling clay are oriented planarly and dispersed in a networkfashion.
 18. The method according to claim 17, wherein a ratio of anarea occupied by said planarly-oriented laminated structures is not lessthan 30% with respect to an area of the longitudinal section of saidcoating film.
 19. The method according to claim 16, wherein a mass ratioof said high hydrogen-bonding resin and said swelling clay is 4:6 to6:4.
 20. The method according to claim 16, wherein said coating materialcomprises a sugar alcohol derivative surfactant.